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The optimum timing to wean invasive ventilation

for patients with AECOPD or COPD with
pulmonary infection
This article was published in the following Dove Press journal:
International Journal of COPD
14 March 2016
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Yuanlin Song, 1 Rongchang Abstract: COPD is characterized by a progressive decline in lung function and mental and
Chen, 2 Qingyuan Zhan, 3 physical comorbidities. It is a significant burden worldwide due to its growing prevalence,
Shujing Chen, 1 Zujin Luo, 4 comorbidities, and mortality. Complication by bronchial-pulmonary infection causes 50%–90%
Jiaxian Ou, 1 Chen Wang 3 of acute exacerbations of COPD (AECOPD), which may lead to the aggregation of COPD
symptoms and the development of acute respiratory failure. Non-invasive or invasive ventila-
1
Department of Pulmonary Medicine,
Zhongshan Hospital, Fudan University, tion (IV) is usually implemented to treat acute respiratory failure. However, ventilatory support
Shanghai, 2Guangzhou Institute of (mainly IV) should be discarded as soon as possible to prevent the onset of time-dependent
Respiratory Disease, Guangzhou, complications. To withdraw IV, an optimum timing has to be selected based on weaning assess-
3
Department of Respiratory and
Critical Care Medicine, Beijing ment and spontaneous breathing trial or replacement of IV by non-IV at pulmonary infection
China-Japan Friendship Hospital, control window. The former method is more suitable for patients with AECOPD without
4
Department of Pulmonary Medicine,
significant bronchial-pulmonary infection while the latter method is more suitable for patients
Chaoyang Hospital, Beijing, People’s
Republic of China with AECOPD with acute significant bronchial-pulmonary infection.
Keywords: mechanical ventilation, weaning, spontaneous breathing trial, pulmonary control
window, chronic obstructive pulmonary disease

Video abstract Introduction

COPD is characterized by a progressive decline in lung function and mental and physi-
cal comorbidities (eg, depression, dystrophy, and heart failure).1 An exacerbation of
COPD is an acute event caused by several factors. To those patients who need ventilator
support because of lung infection, weaning mechanical ventilation may be particularly
difficult. The clinician’s concern is the optimum timing regarding the condition of
the patient to wean mechanical ventilation. Unfortunately, there is no consensus or
guideline that can give us a distinct conclusion. The aim of this paper is to summarize
the evidence-based optimum timing to wean invasive ventilation (IV) in patients with
acute exacerbations of COPD (AECOPD) or COPD with pulmonary infection.

Point your SmartPhone at the code above. If you have a

QR code reader the video abstract will appear. Or use: COPD and its AECOPD and lung infection in COPD
http://youtu.be/KNFo236SFqA COPD is currently a significant burden in the People’s Republic of China because
of greater risk exposure and uneven medical resource allocation between urban and
remote areas. A population-based, cross-sectional survey conducted between 2002 and
Correspondence: Chen Wang 2004 suggested a COPD prevalence of 8.2% among Chinese population over 40 years
Department of Respiratory and
Critical Care Medicine, Beijing
old.2 Other studies reported varied prevalence ranging from 5% to 13%.3–6 According
China-Japan Friendship Hospital, to the 2004 Global Burden of Disease study, an annual sum of 3 million people die of
2 East Yinghua Road, Beijing, 100029,
People’s Republic of China
COPD worldwide. In the People’s Republic of China alone, COPD-related mortality
Email cyh-birm@263.net was 27.3 in males and 21.3 in females per 100,000 heads according to a national,
submit your manuscript | www.dovepress.com International Journal of COPD 2016:11 535–542 535
Dovepress © 2016 Song et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php
http://dx.doi.org/10.2147/COPD.S96541
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hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission
for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Song et al
prospective cohort study conducted between 1990 and 2000.
Acute chronic respiratory failure, heart failure, pulmonary
infection, pulmonary embolism, cardiac arrhythmia, and
lung cancer are the major causes of death in patients with
COPD according to a cross-sectional study involving ten
European centers.7
AECOPD are a common cause of comorbidities and COPD-
related mortality.8–11 They are characterized by an increase in the
symptoms of dyspnea, sputum volume, and sputum purulence
with or without symptoms of upper respiratory infection.12
They may also involve worsening of existing symptoms, which
require alterations in treatment ranging from antibiotic admin-
istration, short courses of oral corticosteroids, and increased
bronchodilator usage.13–14 Reported AECOPD incidence varied
between 2.5 and 3 episodes per patient and year.15 Being its
major cause, infection accounted for 50%–70% AECOPD
occurrences worldwide and 80%–90% AECOPD occurrences
in the People’s Republic of China alone.16,17 Other predisposing
factors include environmental pollution, low temperatures, and
concomitant heart failure.18,19 Subsequent onset of acute respi-
ratory failure (ARF) may result if AECOPD are accompanied
by bronchial infections, bronchospasm, left ventricular failure,
pneumonia, pneumothorax, or thromboembolism. Once ARF
occurs, in-patient mortality (4%–30%) substantially rise up to
50% among elderly patients and 11%–26% among intensive
care unit (ICU) patients.10,20–23
Lung infection other than acute exacerbation is quite
common in patients with COPD. The most prevalent form
is community-acquired pneumonia. Bronchoscopic studies
have shown that at least 50% of patients have bacteria exis-
tence in their lower airway during exacerbations of COPD.1
Viruses are also the common etiology of COPD exacerba-
tion next to bacteria. Many patients with COPD who have
comorbidities such as hypertension, diabetes, cardiovascular
Table 1 Indications for non-invasive ventilation (NIV) and invasive ventilation (IV)
NIV indications
Clinical manifestations
Moderate to severe dyspnea
Respiratory rate over 25 breaths/min
Obvious use of accessory muscles
Paradoxical breathing
Gas-exchange abnormalities
PaCO2 exceeding 45 mmHg
pH below 7.35
PaO2/FiO2 below 250 mmHg
Abbreviations: FiO2, fraction of inspired oxygen; PaO2, partial pressure of oxygen in arterial blood; PaCO2, partial pressure of carbon dioxide in arterial blood.
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disease are susceptible to lung infection. As stated earlier,
lung infection usually accounts for 50%–70% of AECOPD.
Not all lung infections in COPD need intensive care. Only
the patients who meet the criteria for hospital admission or
ICU admission need to be treated in a timely manner.
Treatment for AECOPD/COPD with lung
infection patients
Hospital admission is warranted in an increasing number
of patients with AECOPD to prevent ARF onset.24 An
“ABC approach” involving antibiotics, bronchodilators,
and corticosteroids is generally extended to maximize
lung function and to reverse the predisposing causes of
exacerbations.25 Mechanical ventilation is also suggested
in 26%–74% of patients with COPD so that the respiratory
muscle load may be alleviated to reduce dyspnea and
respiratory rate and improve arterial oxygenation, partial
pressure of carbon dioxide in arterial blood (PaCO2), and
pH.26–28 The criteria to start ventilatory support vary but
commonly involve the following: 1) moderate to severe dys-
pnea where accessory muscles are recruited and abdominal
breathing prevails; 2) hypercapnic acidosis (pH ,7.35);
3) tachypnea (.25 rpm).29
Non-invasive ventilation (NIV) is validated in patients
with early AECOPD because their tolerable coughing ability
suggests a stronger need for respiratory muscle fatigue relief
rather than airway clearance. It is thus initially provided for
patients with severe AECOPD with respiratory acidosis to
reduce intubation rate, shorten ICU stay, and decrease patient
mortality. Nonetheless, IV is indicated if NIV measures fail
to improve clinical manifestation and blood gas parameters
1 hour after implementation.29 Any patient with ineffective
airway clearance (eg, post-surgical patients or patients with
COPD with hypercapnic ARF and pneumonia) needs IV
IV indications
Cardiac/respiratory arrest
Non-respiratory organ failure
Severe upper gastrointestinal bleeding
Hemodynamic instability
Unstable cardiac arrhythmia
Facial surgery
Facial trauma or deformity
Upper airway obstruction
Inability to cooperate
Airway protection
Clear of secretions and saliva
A high risk of aspiration
International Journal of COPD 2016:11
Dovepress AECOPD or COPD patients with pulmonary infection

support to improve sputum discharge and ventilation. Table 1 optimal time when NIV should replace IV. According to the
summarizes the indications for both ventilation types.30 Chinese Guideline for Mechanical Ventilation in Patients
In spite of its importance, IV should be discarded when- with Acute Exacerbation of Chronic Obstructive Pulmonary
ever appropriate to avoid time-dependent complications Disease 2007, weaning with T-tube is advised in COPD
associated with intubation, tracheotomy, or ventilation patients without obvious bronchial-pulmonary infection
(Table 2).31–33 To derive optimum advantages from mechani- while replacement by NIV at pulmonary infection control
cal ventilation, one should identify the optimum timing for (PIC) window is advised in COPD patients with obvious
withdrawal so that complications may be prevented while bronchial-pulmonary infection.
respiratory function is restored. NIV has been suggested
to serve the purpose because it was identically capable in Weaning in COPD patients without
unloading respiratory muscles.34 Its application after IV also obvious bronchial-pulmonary infection
significantly reduced weaning time, alleviated ventilator- Tobin summarized six stages in mechanical ventilatory
associated complications, and improved survival. 35–37 support: 1) treatment of ARF; 2) suspicion that weaning
However, no consensus has yet been reached regarding the may be possible; 3) assessment of readiness to wean;
4) spontaneous breathing trial (SBT); 5) extubation; and
Table 2 Complications associated with intubation, tracheotomy, 6) reintubation when required. One is only liberated from
or ventilation IV when he successfully passes the first five steps and
Common complications of intubation and tracheotomy avoids the last.
Airway complications Weaning accounts for almost half of the time in
Laryngeal edema
mechanical ventilation and allows resumption of spontaneous
Tracheal mucosal trauma
Contamination of the lower respiratory tract breathing after gradual reduction of mechanical support.38–42
Loss of humidifying function of the upper airway Randomized and non-randomized historical cohort studies
Common complications of mechanical ventilation verified a more significant reduction in the duration of
Mechanical complications mechanical ventilation when a weaning protocol, involving
Accidental disconnection
Leaks in the ventilator circuit
weaning parameter evaluation and subsequent breathing
Loss of electrical power trials, was used instead of mere clinical judgment.43–46 In view
Loss of gas pressure of general delays in weaning and the associated increase in
Pulmonary complications
mortality,41,47,48 assessment should be performed every day
Ventilator-induced lung injury
Barotrauma to allow prompt initiation of weaning.
Oxygen toxicity Variations exist between protocols but weaning param-
Atelectasis eters essentially stem from observations in respiratory
Nosocomial pneumonia
mechanics, gas exchange, and breathing patterns. Table 3 is
Inflammation
Auto-PEEP a list of parameters to be considered before weaning.47 Daily
Asynchrony screen of weaning parameters was found to have predicted a
Acid–base complications successful extubation with 82% accuracy, nearly 90% sensi-
Respiratory acidosis
Respiratory alkalosis
tivity and positive predictive values. Significance of passing
Cardiovascular complications the screen could also be extended to hospital survival predic-
Reduced venous return tion during the 1st week and a half of mechanical ventilation.
Reduced cardiac output
Its prognostic significance seemed to be limited though, since
Hypotension
Gastrointestinal and nutritional complications up to 29% of the patients failed the screen but withstood
Gastrointestinal bleeding extubation.49 Thus, a successful weaning attempt does not
Malnutrition necessarily require fulfillment of all the mentioned criteria.
Renal complications
SBT is usually granted to a patient who has passed the
Reduced urine output
Increase in antidiuretic hormone (ADH) and decrease weaning assessment. SBT failure is defined by 1) objec-
in atrial natriuretic peptide (ANP) tive indices such as tachypnea, tachycardia, hypertension,
Neuromuscular complications hypotension, hypoxemia or acidosis, and arrhythmia; 2) sub-
Sleep deprivation
Increased intracranial pressure
jective indices such as agitation or distress, depressed mental
Critical illness weakness status, diaphoresis, and evidence of increasing effort.47 Subse-
Abbreviation: PEEP, positive end-expiratory pressure. quently, weaning failure refers to SBT failure or the need for

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Song et al
Table 3 Assessment of weaning parameters
Clinical assessment
Objective measurement
Abbreviations: BP, blood pressure; fc, frequency of cardiotach; FiO2, fraction of inspired oxygen; fR, frequency of respiration; MIP, maximal inspiratory pressure; PaO2, partial
pressure of oxygen in arterial blood; PEEP, positive end-expiratory pressure; SaO2, arterial oxygen saturation; VT, tidal volume.
reintubation within 48 hours of extubation.50,51 According to
the number of attempts or days prior to successful weaning,
patients may be classified into three groups:47 1) simple wean-
ing (patients who proceeded from initiation of weaning to
extubation on the first attempt without difficulty); 2) difficult
weaning (patients failing the first attempt who took up to three
attempts or as long as 7 days from the first SBT to achieve
successful weaning); and 3) prolonged weaning (patients who
failed at least three weaning attempts or required .7 days of
weaning after the first SBT). Independent factors suggestive
of prolonged weaning include COPD occurrence,47 higher
PaCO2 and heart rate during the first SBT.52 Sellares et al
also found a higher PaCO2 and heart rate among prolonged
weaning patients before their first SBT, implying their worse
condition when subjected to the initial trial.52
SBT is commonly delivered via pressure support ven-
tilation (PSV) at 7 cm H2O, continuous positive airway
pressure, or T-piece. A conventional protocol-directed SBT
takes 120 minutes but a 30 minutes trial performed via either
T-tubes or PSV was found to be equally effective in iden-
tifying successful extubations.44,53 Comparing the delivery
frequency, once-daily and multiple-daily T-piece trials were
found to be equally effective.50 Consensus has also been
established over the identical validity of pressure support
and T-tube in SBT.54 A similar conclusion was valid among
infants and children when pressure support was 10 cm H2O.55
Further to these findings, pressure support was found to over-
run T-tube in difficult-to-wean patients since success of the
former and failure of the latter regardlessly indicated suc-
cessful extubation with unchanged reintubation rate.56 Indeed,
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1. Adequate cough
2. Absence of excessive tracheobronchial secretion
3. Resolution of disease acute phase for which the patient was intubated
4. Clinical stability
Stable cardiovascular status (ie, fc #140 beats/min), systolic BP 90–160 mmHg,
no or minimal vasopressors
Stable metabolic status
5. Adequate oxygenation
SaO2 .90% on FiO2 0.4 (or PaO2/FiO2 $150 mmHg)
PEEP #8 cm H2O
6. Adequate pulmonary function
fR #35 breaths/min
MIP #-20 to -25 cm H2O
VT .5 mL/kg
fR/VT ,105 breaths/min/L
No significant respiratory acidosis
7. Adequate mentation
8. No sedation or adequate mentation on sedation (or stable neurologic patient)
pressure support might have surpassed T-tube because it
compensated for the extra breathing workload caused by an
endotracheal tube.57–61 In addition, Cabello et al observed
more successful pressure support trials in difficult-to-wean
patients when positive end-expiratory pressure (PEEP; 5 cm
H2O) was incorporated to PSV.62 This could be explained by
the abilities of PEEP to 1) reduce respiratory muscle energy
expenditure;63 2) attenuate intrinsic PEEP so that the work
of breathing required to trigger the ventilator reduces;64,65
and 3) decrease pulmonary artery occlusion pressure.62 For
the past few years, computer-driven automated weaning
was introduced to perform SBT automatically in intubated
patients but its value remained questionable from results of
different studies.66 Generally, the technology failed to facili-
tate weaning in surgical patients but prevailed in difficult-
to-wean patients,67 such as those with COPD, ischemic heart
disease, and immunosuppresion.68,69
NIV has been proposed as an alternative weaning tool
in COPD patients who failed SBT. According to a number
of randomized controlled studies and meta-analysis, such
application was associated with reduced mechanical ventila-
tion, shortened ICU and hospital stay, decreased incidence
of septic shock, and pneumonia and improved survival.35,37,70
Theoretically speaking, extubated patients administered with
NIV should not be declared as weaning success unless they
ultimately get rid of the ventilatory support. Increased use of
NIV as a weaning tool thus leads to a new weaning category
called “weaning in progress” wherein extubated patients con-
tinue to be supported by NIV. In spite of its benefits among
COPD patients, NIV should not be indicated in all patients
International Journal of COPD 2016:11
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Table 4 Standard of the PIC window
Indexes
Imaging change
Ventilator settings
Body temperature
Leukocyte count
Sputum quantity
Lightening of sputum color
Decreased density of sputum
Abbreviations: PIC, pulmonary infection control; PSV, pressure support ventilation; SIMV, synchronized intermittent mandatory ventilation.
failing SBT because they may be exposed to extubation
failure due to substantial comorbidities.47
To summarize, the amount of time needed for IV libera-
tion depends on a sequence of events including suspicion for
weaning possibility, performance of weaning assessment,
and weaning itself. In order to promptly discard ventilatory
support, weaning assessment is daily performed in ventilated
patients. When SBT fails in selected COPD patients, NIV
may be recruited to shorten the duration of IV.
Replacement of invasive ventilation by
non-invasive ventilation at PIC window
In the People’s Republic of China, 80%–90% AECOPD
cases occur as a result of bronchial-pulmonary infection. A
significant proportion of them further develop into hyper-
capnic respiratory failure which requires invasive ventilatory
support. In order to restore respiratory function and avoid
time-dependent complications, studies are being conducted
to search for an optimum timing to discard IV.
PIC window has been defined as a prompt stage of con-
trolled pulmonary infection following artificial airway estab-
lishment, sputum drainage, and antibiotic administration.
It was marked by thinning and decrease of sputum; clear-
ing of sputum cloudiness; decreases in body temperature,
radiographic infiltrations, and leukocytes (Table 4).17 At this
stage, COPD patients with severe hypercapnic respiratory
failure tend to be more stable and respiratory muscle fatigue
becomes relatively more significant in the development of
respiratory failure.17 Wang et al17 proposed this stage as an
optimum timing to replace IV with NIV so that ventilatory
insufficiency and respiratory muscle fatigue may be resolved
while lower airway infection and ventilator-associated
pneumonia can be avoided. Such a hypothesis was veri-
fied through a prospective cohort study and a prospective,
multi-centered, randomized controlled trial among COPD
patients with severe hypercapnic respiratory failure. 71–73
In both research plans, the study groups were liberated
International Journal of COPD 2016:11
AECOPD or COPD patients with pulmonary infection
Evaluation
Significantly decreased radiographic infiltrations
10–12 beats/min for SIMV
10–12 cm H2O for PSV
#38°C
,10,000/mm3 or 2,000/mm3 less than before
Significantly reduced
Changed to white
,II (second level)
from IV in exchange for NIV at PIC window while the
control groups proceeded with IV throughout. By the end
of the trials, the study groups were found to possess lower
ventilator-associated pneumonia risks and mortality rate
while requiring shorter durations of IV, ventilatory support,
and ICU stay.17,74 Another study with nine patients yielded
similar results except in two patients who presented with
unstable hemodynamic condition and consciousness distur-
bance correspondingly.75
While the significance of PIC window has been verified,
one should be reminded of how proper training, skills, and
observation ascertain the identification of such a stage. Zhang
failed to recognize PIC window in several clinical cases thus
led to delay in response and subsequently compromised prog-
nosis and increased medical costs.75 An increased intubation
rate has also been associated previously with inexperienced
labor among hypercapnic ARF patients.76,77 Such results
suggested how proper caring and observation hold the key
to the betterment of all ventilated patients above other clini-
cal advancements.
Conclusion
Ventilatory support is essential among AECOPD patients to
prevent and treat ARF. While NIV is increasingly suggested
as a primary option, IV may not be avoided under certain
conditions. In such cases, strategies should be implemented
to discard IV as soon as possible so that time-dependent
complications may not arise as a result of prolonged IV.
In AECOPD patients, weaning by SBT (assisted with NIV)
is suggested under insignificant bronchial-pulmonary infec-
tion while replacement by NIV at PIC window is encouraged
under significant bronchial-pulmonary infection.
Acknowledgments
The work was supported by the National Key Technology
R&D Program of the 12th National Five-year Development
Plan (2012BAI05B01 and 2012BAI05B02), the National
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539
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Song et al
Nature Science Foundation of China (81170056, 81400018,
and 81400002), the Shanghai Committee of Science and
Technology (11411951102 and 12JC1402300), and the
Academic Special Science and Research Foundation for PhD
Education (20130071110044).
Disclosure
The authors report no conflicts of interest in this work.
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